tbuckley/cabot-search huggingface dataset:
Abstract 13473: Impaired Atrial Natriuretic Peptide Potency in Human Acute Decompensated Heart Failure and Therapeutic Potential of a Novel Designer Peptide (MANP) Using an Innovative Ex-Vivo Precision Medicine Assay
Authors: Shawn H Reginauld, Ye Zheng, Dante Moroni, Xiao Ma, Horng Chen, Valentina CANNONE, Jeson Sangaralingham, John C Burnett
Journal: Circulation (2022)

Introduction: Atrial natriuretic peptide (ANP) is the most potent endogenous activator of the guanylyl cyclase A receptor (GC-A) mediating cardiorenal protective actions by increasing cGMP production. To test the hypothesis that acute decompensated heart failure (ADHF) is associated with increased circulating ANP but with reduced GC-A potency, we developed an ex-vivo precision medicine assay to quantify the potency of circulating ANP in plasma from healthy and ADHF subjects. Further, we assessed the ex-vivo potency of MANP, a novel ANP analog with greater cGMP activation than ANP, also using plasma of healthy and ADHF subjects. Methods: For the potency assay, we engineered HEK293 cells to overexpress human GC-A. Plasma from individual healthy (n=4) and ADHF (n=4) subjects was incubated in the assay and cGMP was assessed. The endogenous ANP derived cGMP was evaluated against the cGMP response of equimolar synthetic ANP (S ANP ) to assess potency of ANP from each cohort. MANP mediated cGMP generation was also assessed in the assay using healthy and ADHF plasma. Results: Healthy plasma, in which plasma ANP was 26±5 pg/mL, generated 10.3±0.7 pmol/mL of cGMP. S ANP added to the assay to mimic endogenous ANP levels in healthy subjects produced 7.8±0.5 pmol/mL of cGMP. ADHF plasma with markedly elevated ANP (350±57pg/mL) generated 23.5±3.1 pmol/mL of cGMP. S ANP mimicking plasma ANP in ADHF produced 59.7±13.8 pmol/mL of cGMP, which was greater than cGMP generated from ADHF patient-derived plasma (p&lt;0.05), consistent with reduced potency of endogenous ANP in ADHF. Low treatment dose of MANP (LD MANP ; 10 -8 M) in healthy plasma increased cGMP to 45±5.5 pmol/ml while high treatment dose (HD MANP ; 10 -6 M) increased cGMP to 167.1±14.1 pmol/mL. In markedly elevated ANP ADHF plasma, LD MANP increased cGMP to 60.4±9.7 pmol/mL while HD MANP increased cGMP to 200.8±5.4 pmol/mL (p&lt;0.03 for both) demonstrating similar cGMP production by MANP in healthy and ADHF plasma. Conclusions: Employing a novel ex-vivo precision medicine ANP/GC-A/cGMP assay, we conclude that ADHF is characterized by elevated ANP yet with impaired potency in GC-A activation and cGMP generation. MANP overcomes this impairment and serves as a potential efficacious GC-A activating therapeutic in heart failure.
Abstract 13075: Hemodynamic Estimation of Personalized Initial Target Heart Rate in Patients With Atrial Fibrillation With Rapid Ventricular Response
Authors: Chee Jeon Kim
Journal: Circulation (2022)

Introduction: Rate control in atrial fibrillation (AF) has played a pivot role in clinical setting even though recent advances in rhythm control. There are few evidences for target heart rate in either acute or chronic situations. Hypothesis: This study tried to estimate personalized initial target heart rate based on hemodynamic assessment in patient with AF with rapid ventricular response. Methods: A total of 72 patients with AF were included. From the equation between preceding RR interval and left ventricular peak ejection velocity adjusted by pre-preceding RR interval, the relationship between cardiac performance representing cardiac output and heart rate was calculated, and heart rate showing maximal cardiac performance (HRmax) was obtained (Left Figure). Results: Mean HRmax was 126±21.8/min (from 75/min to 188/min). Three-fourth patients had HRmax &gt;120/minute (Right Figure). The relationship between Vpe and preceding RR interval showed two types, biphasic or monophasic resulting in similar patterns between cardiac performance and heart rate (Left Figure). HRmax &lt;100/min was found in 7 patients in whom left ventricular dilatation, dysfunction, and/or aortic regurgitation were observed (Left Figure C). Lower HRmax was independently associated with larger aorta size (r=0.48, p&lt;0.001), the absence of mitral regurgitation (r=0.43, p&lt;0.005), prescription of angiotensin converting enzyme inhibitor or angiotensin receptor blocker (r=0.39, p=0.001), and a history of heart failure (r=0.21, p=0.019). Conclusions: In most AF patients, hemodynamic approach suggested that tachycardia of 120/min or more is tolerable. The method of this study may be useful to deliver individually designed management by identifying patient that strict rate control is mandatory. In other patients, management of underlying causes for tachycardia is enough without medications for mechanical heart rate control to avoid adverse effects without clinical benefits.
Abstract 14030: Characterization of Lipid Profiles, Lipid Management Medications, Medical Resources Utilization and Health Care Outcomes in Medicare Age Patients With COPD in an Academic Center
Authors: Mukul Bhattarai, Radhika Deshpande, Raj Patel, Manjari R Regmi, Abhishek Kulkarni, Mark Graves
Journal: Circulation (2022)

Introduction: Recent studies have shown dysregulation in lipid metabolism may contribute to various lung diseases including COPD. The lipid profile in patients with COPD is incompletely understood which may affect the clinical outcomes. Objective: To perform elaborative investigation on lipid profile in COPD patients and clinical outcomes Methods: A retrospective database reviews from single academic medical center Results: The study population included 1360 patients, over the age of 65 with a diagnosis of COPD in a 2-year period. The presence of coronary artery disease, cerebrovascular disease, and peripheral artery disease was measured. The variables measured include lipid profile, lipid medications, number of hospitalizations, number of clinic and emergency room visits (Table 1). 38% of COPD patients have cardiovascular disease (CVD) compared to the prevalence of vascular disease in the population as a whole (27%). The average triglyceride (TG) in the patients with COPD was greater than TG in patients without COPD (150 vs. 135, p=.03). 38% of COPD patients with CVD have a TG &gt; 150. 19% of COPD patients with coexisting vascular disease had an LDL &gt;100. Anti-lipid medications in COPD patients were sub-optimally utilized. Conclusions: COPD patients had poorly controlled lipid profile including elevated TG and LDL levels. These patients are at high risk for adverse events that include CVD, frequent ER visits and hospital readmission. The anti-lipid medications were underutilized. It is highly recommended to identify barriers to optimum care and seek resources and strategy to mitigate difficulties in lipid management in patients with COPD to prevent adverse outcomes.
Abstract 14060: SGLT2 Inhibitors in Patients With Overweight or Obesity: Systematic Review and Meta-Analyses
Authors: Muhammad Shariq S Usman, Mohammad S Khan, Hasan F Siddiqui, Shazil A Gangat, Tariq Siddiqi, Michael E Hall, Sushil A Luis, Marat Fudim, Richard Krasuski, Darren K McGuire, Javed Butler
Journal: Circulation (2022)

Background: RCTs studying the effect of sodium-glucose co-transporter 2 inhibitors (SGLT2i) on cardiovascular (CV) risk factors and outcomes have been underpowered to assess patients with overweight or obesity, thus presenting the need for a meta-analysis. Methods: Electronic databases were queried up till February 2022 for RCTs comparing SGLT2i with placebo in patients with overweight (BMI ≥25 kg/m2) or obesity (BMI ≥30 kg/m2) - irrespective of diabetes status - with a follow-up of ≥24 weeks. Meta-analyses were performed using the generic inverse variance technique and a random-effects model. Results are presented as weighted mean differences (WMD) for continuous outcomes, and hazard ratios (HR) for dichotomous outcomes. Outcomes studied were: (i) weight; (ii) systolic BP; (iii) diastolic BP; (iv) heart rate; (v) HDL-C; (vi) LDL-C; (vii) major adverse cardiac events (MACE), i.e., composite of CV death, non-fatal myocardial infarction (MI) and non-fatal stroke; (viii) composite of heart failure hospitalization and CV death (HFH/CV death); (ix) mortality; (x) MI; and (xi) stroke. Results: Seventeen RCTs (47,649 patients) were included. Compared with placebo, SGLT2i significantly reduced weight (WMD: -2.32 kg [-2.77, -1.88]), HbA1c (WMD: -0.79 % [-0.98, - 0.61]) and systolic BP (WMD: -2.15 mm Hg [-3.08, - 1.22]). SGLT2i did not have a significant effect on diastolic BP (WMD: -0.55 mmHg [-1.51, 0.41]), heart rate (WMD: 0.08 bpm. [-0.21, 0.37]), HDL-C (WMD: 1.62 mmol l -1 [-0.21, 3.45]) or LDL-C (WMD: 0.53 mmol l -1 [-0.88, 1.94]). Amongst CV outcomes, SGLT2i reduced the risk of MACE (HR: 0.90 [0.81, 0.99]), HFH/CV death (HR: 0.82 [0.75, 0.90]), and mortality (HR: 0.85 [0.77, 0.94]). No effect was noted on stroke (HR: 0.99 [0.85, 1.26]) or MI (HR: 0.89 [0.77, 1.02]). Conclusions: In patients with overweight or obesity, SGLT2i produce a modest but significant reduction in weight, systolic BP and HbA1c. SGLT2i may also reduce the risk of MACE, HFH/CV death, and mortality.
Abstract 12778: Improving Advanced Care Planning for Hospitalized Patients With Heart Failure
Authors: Akash H Patel, Ava Runge, Tobin Mathew, Nathalie De Michelis, Behram Mody
Journal: Circulation (2022)

Introduction: Advanced Care Planning (ACP) is an important and proven strategy to improve end-of-life communication and the quality of life of patients with heart failure and their relatives. However, the frequency of ACP conversations in practice remains low. UCI’s heart failure (HF) metrics show that in the months of April 2021 to October 2021 prior to intervention, an average of 13.24% of HF patients hospitalized at UCI had completed ACP at discharge, as measured by presence of POLST form or Advanced Directive (AD) in Epic. The goal of this quality improvement project was to determine whether the rate of ACP completion could be improved using electronic medical record (EMR) reminders to the healthcare team. Methods: For a 3-month period [January 2022-March 2022], our research team messaged providers designated as ‘First Call’ for each hospitalized patient with a primary diagnosis of HF and no existing ACP documentation in the Epic EMR. Messages were sent via Epic’s secure chat function, serving as a reminder to complete ACP documentation including a POLST form. Messages were sent on the day of admission with a second message sent after 2 weeks if the patient remained hospitalized and there was no change in ACP completion status. Percentage of ACP documentation completion was calculated during the 3-month study period. Results: Our results have demonstrated that the ACP completion was an average of 21.00% during the 3 months of the intervention. This is a 7.76% absolute increase in ACP completion compared to 3 months prior to our intervention (13.24%); a 58.61% relative increase. Conclusions: ACP among hospitalized HF patients remains low. Direct message reminders to providers serves as a beneficial means of improving ACP completion among this subset of patients.
Abstract 13234: Prediabetes, an Important Predictor of Major Adverse Cardiac and Cerebrovascular Events in Atrial Fibrillation Patients: A National Inpatient Sample Analysis, 2019
Authors: Rupak Desai, Adhvithi Pingili, Nishanth Katukuri, Koushik Sanku, BORZOO TAJDIN, Akhila S Cherukuri, HAMIDREZA JALILI, Tamer Zahdeh, Pooriya Bahadoran, Sashwath Srikanth
Journal: Circulation (2022)

Background: Prediabetes is an established risk factor for major adverse cardiac and cerebrovascular events (MACCE). However, the association between prediabetes (pDM) and MACCE in atrial fibrillation (AF) patients remains understudied. We aim to establish a relation between prediabetes and MACCE in AF patients. Methods: Using the National Inpatient Sample (2019) and relevant ICD-10 codes, we identified hospitalizations with AF and categorized them into groups with and without pDM excluding diabetics. The primary outcome was MACCE (All-cause inpatient mortality, Cardiac Arrest including Ventricular Fibrillation, and Stroke) in AF-related hospitalizations. Results: Of 2,965,875 AF-related hospitalizations for MACCE, 47,505 (1.6%) were among pre-diabetics. The pDM cohort was relatively younger (median 75 vs 78 years), often consisted of males (56.3% vs 51.4%), blacks (9.8.% vs 7.9%), Hispanics (7.3% vs 4.3%), and API (4.7% vs 1.6%) than the nonprediabetic cohort (p&lt;0.001). The pDM group often had significantly higher rates of HTN, hyperlipidemia, smoking, obesity, drug abuse, prior MI, PVD, and hyperthyroidism (all p&lt;0.05). The pDM cohort was often discharged routinely (51.1% vs 41.1%) but more frequently required home health care (23.6% vs 21.0%) and had higher costs. After adjusting for baseline characteristics or comorbidities, pDM cohort with AF admissions showed higher rate and significantly higher odds of MACCE vs Non-pDM cohort (18.6% vs. 14.7%, OR 1.34, 95CI 1.26-1.42, p&lt;0.001). On subgroup analyses, Males had stronger association (aOR 1.43) compared to females (aOR 1.22) whereas on race-wise comparison, Hispanics (aOR 1.43) and Asians (aOR 1.36) had stronger association with MACCE with pDM vs. whites (aOR 1.33) and blacks (aOR 1.21). Conclusions: We found a significant association between prediabetes and MACCE in AF patients. There is a need for further research to actively screen and manage pDM in AF to curtail MACCE.
Abstract 13708: Il11 Causes Pulmonary Tissue Remodeling and Emphysematous Lung Disease in the Fbn1 <sup>C1041G/+</sup> Mouse Model of Marfan Syndrome
Authors: Benjamin Ng, Chen Xie, Liping Su, Fathima Farzana F Kuthubudeen, xiuyi kwek, Daryl Yeong, Sebastian Schafer, Stuart Cook, Wei-Wen Lim
Journal: Circulation (2022)

Introduction: Marfan Syndrome (MFS) is an inherited connective tissue disorder caused by fibrillin-1 (FBN1) mutations that is associated with aortic disease. Lung abnormalities are common in MFS, but their pathogenesis is poorly understood. Here we studied IL11 in a mouse model of MFS (mMFS). Methods: We studied histological and molecular phenotypes in the lungs of Fbn1 C1041G/+ (mMFS) mice, an established model of MFS. To identify IL11-expressing lung cell types, we studied 4- and 16-week-old Fbn1 C1041G/+ : Il11 EGFP/+ reporter mice lungs by immunohistochemistry. We studied the protective effects of IL11 inhibition in the lung by RT-qPCR, immunoblots and histopathology in two models: 1) 16-week-old IL11 receptor (IL11RA) knockout mMFS mice ( Fbn1 C1041G/+ : Il11ra1 -/- ) and 2) administered IgG isotype control or anti-IL11RA (X209; 20mg/kg) antibodies twice weekly in mMFS mice between 4 to 24 weeks of age. Results: IL11 was upregulated in the lungs of mMFS mice, which exhibited progressive loss and enlargement of distal airspaces and increased extracellular matrix production. In the distal airways of young mMFS mice (4 weeks old), IL11 was specifically expressed in smooth muscle cells. In the older (16 weeks old) mMFS lungs, IL11 was expressed in smooth muscle cells, fibroblasts and type II alveolar epithelial cells. In mMFS mice, genetic ( Fbn1 C1041G/+ : Il11ra1 -/- mice) or pharmacologic (anti-IL11RA) inhibition of IL11 protected against emphysematous changes, pulmonary fibrosis and inflammation and was associated with reduced pulmonary ERK1/2 signaling and matrix metalloproteinase (MMP2 and MMP9) expression. Conclusions: IL11 causes pulmonary disease in mMFS. This adds to the recent finding that IL11 underlies aortic pathology in mMFS and provides a common disease mechanism across affected tissues in MFS. This has potential implications for treating multi-organ disease in MFS.
Abstract 13749: Association of Left Atrial Hemodynamics by Cardiac Magnetic Resonance With Clinical Outcomes in Patients With Non-Ischemic Cardiomyopathy
Authors: Muhammad S Munir, Mina M Benjamin, Michael Thompson, Parth Shah, Maria Khalil, Menhel Kinno, Mushabbar A Syed
Journal: Circulation (2022)

Introduction: Left atrial hemodynamics are associated with clinical outcomes in a variety of cardiac conditions. We sought to assess the association of LA function and strain by cardiac magnetic resonance (CMR) in patients with non-ischemic cardiomyopathy (NICM) with clinical outcomes. Methods: We retrospectively evaluated 92 patients who were diagnosed with NICM and 50 controls without significant cardiovascular disease who underwent clinically indicated CMR and echocardiography. CMR was used to calculate indexed LA volumes (LAVi), ejection fraction (EF) and expansion index as well as measure LA reservoir (εR), conduit (εCD), and contractile strain (εCT). A multivariate regression analysis was performed with an endpoint of heart failure hospitalization (HFH). Results: Mean age for NICM patients was 59.6 ± 15.9 (64% males, 73% whites) versus 52.2 ± 12.4 (34% male, 64% white) for controls. Median follow-up was 58.9 months (IQR 57.1). LA EF and all LA strain components were significantly lower in NICM compared to controls (Table 1). On univariate analysis, mitral regurgitation, left and right ventricular EF, late gadolinium enhancement, εR, εCD, minimum and maximum LAVi were significantly associated with HFH. On multivariate analysis, after adjusting for the factors above and entering the LA parameters one at a time, εR was the only factor significantly associated with HFH (OR 0.98, CI 0.96-1.0). Adjusted Cox proportional hazard model for εR dociles (Median εR ~ 18) had a significant χ2 statistic of 21.1, p=0.03 (Figure). Conclusion: LA strain was significantly reduced in patients with NICM. Among all LA strain components, only εR was independently associated with HFH.
Abstract 13185: Incidence and Risk Factors of Acute Cardiovascular Complications After Hematopoietic Stem Cell Transplantation
Authors: Alexi Vasbinder, Elizabeth Anderson, Tonimarie Catalan, Catherine Chu, Megan Kotzin, Tariq Azam, Daniel Perry, Husam Shadid, Matthew Rochlen, Sarah Yentz, Bryan Schneider, Monika Leja, Christopher Lao, Leslie Fecher, Sunita Nathan, Tochi Okwuosa, Salim Hayek
Journal: Circulation (2022)

Introduction: Hematopoietic stem cell transplantation (HSCT) is associated with various cardiovascular (CV) complications. Due to the lack of recent large cohort studies, the incidence and clinical determinants of acute HSCT-related CV events are ill-defined. Methods: We conducted a multi-center observational study (University of Michigan and Rush University) of adult (≥18 years) patients who underwent autologous or allogeneic HSCT for malignant or non-malignant bone marrow disorders from 2005-2021. Data on demographics, pre-HSCT clinical characteristics, imaging, laboratory findings, and acute (&lt;100 days post-HSCT) CV outcomes were collected through manual chart review. The primary outcome was defined as a composite of death from CV cause, non-fatal myocardial infarction, need for revascularization, new-onset heart failure (HF), new diagnosis of atrial fibrillation/flutter, or sustained ventricular tachycardia. Results: Of 4,262 included patients (mean age at HSCT 56±14 years; 59% male; 82% White), 161 (3.8%) patients experienced an acute CV event (153 events/1,000 person-years). Compared to patients without a CV event, those who developed a CV event were older, had greater burden of CV comorbidities including HF, more likely to be on antihypertensives, statins, and aspirin, and had higher B-type natriuretic peptide and lower high-density lipoprotein pre-HSCT (Table). Pre-HSCT ejection fraction and prior anthracycline exposure were not associated with acute CV events. Conclusions: In the largest cotemporary cohort of adult HSCT patients to date, acute CV events occurred in &lt;5% of patients. Events were more common in older patients with CV comorbidities. highlighting the potential need for improving the pre-HSCT CV risk stratification. The major limitation of this study is the retrospective nature and accompanying selection bias. Future prospective studies should assess evidence-based strategies for risk-stratifying HSCT patients.
Abstract 13063: Clonal Hematopoiesis Associated With TET2 and DNMT3A Gene Driver Mutations Accelerates Aortic Valve Calcification in vitro and in vivo
Authors: Wesley T Abplanalp, Bianca Schuhmacher, Silvia Mas-Peiro, María A Zuriaga, Nuria Matesanz, Jose J Fuster, David John, Marion Muhly-Reinholz, Mariuca Vasa-Nicotera, Maximilian Merten, Jedrzej Hoffmann, Andreas M Zeiher, Stefanie Dimmeler
Journal: Circulation (2022)

Calcific aortic valve disease (CAVD) is the most common age-related heart valve disease, with no medical therapy to halt progression. Age is associated with the enrichment of somatic mutations in hematopoietic stem cells leading to clonal hematopoiesis (CH). CH mutations promote inflammation, occur in more than 30% of patients with severe CAVD and CAVD patients harboring CH mutations have a worse prognosis. Single-cell RNA-sequencing of immune cells (n=127120 cells) of CAVD patients with CH-mutations showed strong proinflammatory and M1-like macrophage gene signatures (CD38, CXCL10) along with genes associated with calcification (S100A9, RUNX2, Oncostatin M=OSM) suggesting that CH might be causally involved in CAVD. Indeed, silencing of TET2 or DNMT3A in macrophages in vitro induce the prototypic osteoblastic transcription factor RUNX2 and paracrine acting genes such as OSM and S100A9, which can promote vascular calcification. Secreted factors from TET2 or DNMT3A-silenced macrophages induced osteoblastic differentiation as demonstrated by elevated calcium deposition and genes involved in the RUNX2 signaling pathway (COL1A2, ALP), which could be ablated by silencing of OSM in CH-macrophages. Atheroprone Ldlr -/- mice receiving TET2 -/- bone marrow transplants mice showed increased total calcified area along (1.49-fold) with increased numbers of calcification deposits (2.33-fold) as evidenced by von Kossa staining. Increased myeloid derived OSM and S100A9 was found in the valves of TET2 -/- BMT mice with S100A9 strongly co-occurring with OSM. This study provides insights into the development of incident CAVD for patients with CH mutations and therefore yields plausible interventions for nearly one third of CAVD cases to slow or stop disease progression.